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Enhanced pharmacological activities of AKR1C3-activated prodrug AST-3424 in cancer cells with defective DNA repair.
- Source :
-
International journal of cancer [Int J Cancer] 2024 Sep 07. Date of Electronic Publication: 2024 Sep 07. - Publication Year :
- 2024
- Publisher :
- Ahead of Print
-
Abstract
- AST-3424 is a novel and highly tumor-selective prodrug. AST-3424 is activated by AKR1C3 to release a toxic bis-alkylating moiety, AST 2660. In this study, we have investigated the essential role of DNA repair in AST-3424 mediated pharmacological activities in vitro and in vivo. We show here that AST-3424 is effective as a single therapeutic agent against cancer cells to induce cytotoxicity, DNA damage, apoptosis and cell cycle arrest at G2 phase in a dose- and AKR1C3-dependent manner in both p53-proficient H460 (RRID:CVCL&#95;0459) and p53-deficient HT-29 cells (RRID:CVCL&#95;0320). The combination of abrogators of G2 checkpoint with AST-3424 was only synergistic in HT-29 but not in H460 cells. The enhanced activity of AST-3424 in HT-29 cells was due to impaired DNA repair ability via the attenuation of cell cycle G2 arrest and reduced RAD51 expression. Furthermore, we utilized a BRCA2 deficient cell line and two PDX models with BRCA deleterious mutations to study the increased activity of AST-3424. The results showed that AST-3424 exhibited enhanced in vitro cytotoxicity and superior and durable in vivo anti-tumor effects in cells deficient of DNA repair protein BRCA2. In summary, we report here that when DNA repair capacity is reduced, the in vitro and in vivo activity of AST-3424 can be further enhanced, thus providing supporting evidence for the further evaluation of AST-3424 in the clinic.<br /> (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Details
- Language :
- English
- ISSN :
- 1097-0215
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 39243400
- Full Text :
- https://doi.org/10.1002/ijc.35170